Applied proteomics: using the peripheral proteome to identify a surrogate marker of schizophrenia
Lead Research Organisation:
King's College London
Department Name: Institute of Psychiatry
Abstract
Schizophrenia is a complex disease about which we understand little. We do know that there are genetic differences in some people with schizophrenia and these differences will almost certainly be reflected in protein changes as well. However schizophrenia is a brain disease, and of course we cannot easily look in the brain for protein changes. Fortunately many of the genes expressed in brain are also expressed in blood, and thus it should be possible to design a blood-based test to help treat the disease. We plan to look for protein changes in the blood of people with schizophrenia. We will use newly developed methods called proteomics and if we find such changes then we will be careful to make sure that these are due to disease and not the drugs used to treat the disease. We will confirm any findings we make but if we do find a difference in proteins in the blood of people with schizophrenia then this may help us to understand the condition and to find better tests for it. Such tests might have real and important benefits for patients.
Technical Summary
Schizophrenia (SZ) is a brain disorder generally considered to be neurodevelopmental in origin but showing some signs of degeneration and some possible biochemical overlap with Alzheimer‘s disease (AD). The aim of this study is to use proteomic techniques to identify and quantify blood-based biomarkers of psychosis in a sample of patients with Schizophrenia. The hypothesis is that psychotic symptoms will correlate with the presence in peripheral blood of markers that reflect ongoing processes in the CNS, extraneural processes or whole-body changes.
A variety of neurological diseases have already benefited from a proteomic approach to biomarkers including AD, Parkinson‘s disease and others. Proteomics is also entering the field of psychiatric research with promising results in affective disorders, substance misuse and, more recently, in psychotic disorders.
Proteomic technologies are capable of identifying candidate biomarkers in cerebrospinal fluid, in human plasma, in urine and in post-mortem tissue, where recent studies have shown differences in the expression of a number of proteins involved in metabolic, structural and functional processes in neurons and glial cell populations. Whilst schizophrenia is clearly a brain disorder it is likely that there will be peripheral changes detectable that either reflect systemic changes associated with disease or that reflect specific changes occurring in the brain. Whatever the mechanism there is some evidence that there are such peripheral changes in SZ just as there are for AD.
We plan to use two complementary approaches to examine the plasma of people with schizophrenia and matched controls. Initially we will use two-dimensional gel electrophoresis coupled to mass spectrometry to identify potential biomarkers and then use a multiplexing mass spectrometry based approach with isotope coded affinity tags to independently confirm these. In both cases we will use an initial test set followed by a replication set. We hypothesise that there will be differences between schizophrenia and controls and furthermore we will identify changes unique to disease and not secondary to prescribed drugs or drugs of abuse. Proteins identified will be confirmed in a larger and independent sample using immuno-detection approaches. Plasma will be analysed by western blot using, whenever possible, commercially available specific primary antibodies or by ELISA. Known target proteins will be examined for their potential influence in the aetiopathogenesis of the disorder.
The outcomes of this research will be improved understanding of schizophrenia and biomarkers that may have use for prediction, for early diagnosis or, most promisingly, as surrogates of disease
A variety of neurological diseases have already benefited from a proteomic approach to biomarkers including AD, Parkinson‘s disease and others. Proteomics is also entering the field of psychiatric research with promising results in affective disorders, substance misuse and, more recently, in psychotic disorders.
Proteomic technologies are capable of identifying candidate biomarkers in cerebrospinal fluid, in human plasma, in urine and in post-mortem tissue, where recent studies have shown differences in the expression of a number of proteins involved in metabolic, structural and functional processes in neurons and glial cell populations. Whilst schizophrenia is clearly a brain disorder it is likely that there will be peripheral changes detectable that either reflect systemic changes associated with disease or that reflect specific changes occurring in the brain. Whatever the mechanism there is some evidence that there are such peripheral changes in SZ just as there are for AD.
We plan to use two complementary approaches to examine the plasma of people with schizophrenia and matched controls. Initially we will use two-dimensional gel electrophoresis coupled to mass spectrometry to identify potential biomarkers and then use a multiplexing mass spectrometry based approach with isotope coded affinity tags to independently confirm these. In both cases we will use an initial test set followed by a replication set. We hypothesise that there will be differences between schizophrenia and controls and furthermore we will identify changes unique to disease and not secondary to prescribed drugs or drugs of abuse. Proteins identified will be confirmed in a larger and independent sample using immuno-detection approaches. Plasma will be analysed by western blot using, whenever possible, commercially available specific primary antibodies or by ELISA. Known target proteins will be examined for their potential influence in the aetiopathogenesis of the disorder.
The outcomes of this research will be improved understanding of schizophrenia and biomarkers that may have use for prediction, for early diagnosis or, most promisingly, as surrogates of disease